Tumor necrosis factor (TNF) is a pro-inflammatory cytokine which is produced by a wide spectrum of cells. It has a key role in host defense and immunosurveillance, mediating complex cellular responses. In excess, TNF may have detrimental effects.
Two specific, high affinity cell surface receptors, p55 TNF-R and p75 TNF-R, function as transducing elements, providing the intracellular signal for cell responses to TNF. While both types of TNF receptors are expressed by almost all cell types, the p75 receptor has been shown to be expressed primarily by cells of the immune system (B and T cells), cells of myeloid origin, and endothelial cells. Both receptors participate in the induction of NF.kappa.B and interleukin-6, in the generation of lymphocyte activated killer (LAK) cells, and in the proliferation of natural killer (NK) cells, as well as in anti-proliferation, cytotoxicity, and apoptosis.
TNF signaling to cells is largely mediated by the p55 TNF-R, while the main function of the p75 surface receptor is "ligand passing," i.e., TNF presentation to the p55 TNF-R. Presence of the cell surface p75 TNF receptor greatly enhances the rate of association of TNF to the p55 TNF receptor and may reverse the desensitization of p55 TNF-R to TNF. Pharmaceutical agents which affect p75 TNF-R may have a general impact on TNF function, including those activities in which the major signaling receptor is the p55 TNF-R.
The TNF-Rs also mediate many non-overlapping functions: the p55 receptor is involved in interleukin-2 receptor induction, anti-viral activities, growth stimulation, HLA antigen expression, and endothelial cell adhesion, while the p75 receptor mediates the TNF-induced thymocyte proliferation.
The p55 and p75 TNF-Rs are members of a superfamily which includes nerve growth factor receptor (NGFR), Fas antigen, CD27, CD30, CD40, OX40 and 4-1BB. The cysteine-rich domains of the extracellular part of these receptors are homologous to several viral proteins produced by cowpox virus, Shope fibroma virus, and the myxoma virus.
Because of the central role of TNF and its receptors in host defense and immunosurveillance, there is a need in the art to identify new members of the TNF and TNFR superfamilies.